Effector trogocytosis is induced by tumor-derived substances, and CAR T cells are blocked.

The immune system is prepared to fight off internal threats like cancer in addition to exterior invaders like viruses, bacteria, and parasites. However, cancers routinely avoid detection and outsmart the immune system’s defences.

According to a recent study, conducted by Serge Y. Fuchs of the School of Veterinary Medicine, cancers can avoid both the immune system and cancer treatments that depend on it, including CAR T cells that have been genetically altered.

Their study, which was published in the journal Cell Metabolism, demonstrated how tumor-derived substances promote trogocytosis, a procedure named after the Greek verb trogo, which means “to chew” or “to gnaw.” T cells can occasionally “nibble” a portion of the cancer cell membrane when they engage with the cancer cells. The T cells may start expressing that antigen on their own cell surface, making it seem to other T cells like a cancer cell, if that membrane segment contains an antigen, a chemical particular to the tumour.

Trogocytosis can impact both the patient’s own T cells and those that have been altered to become CAR T cells, a treatment in which the patient’s T cells are genetically modified to target cancer cells specifically, cultured in a lab, and then returned to the patient.

Fuchs and colleagues have long been interested in how immune cell surface receptors direct anti-cancer immunity, and they have produced a number of findings demonstrating how cancers can manipulate T cells to avoid being targeted and killed.

Tumor-derived factors, or the mixture of proteins, lipids, and other substances that cancer cells exude into the body, are of particular interest. The Penn scientists discovered that the T cells’ capacity to combat cancer was compromised when these secretions were collected and exposed to the resultant solution.

They simply died more frequently, trogocytosed more, and killed fewer cancer cells as a result of being exposed to this tumor-conditioned medium.

Serge Fuchs is the Elizabeth and William Whitney Clark Professor of Oncology at the University of Pennsylvania School of Veterinary Medicine.

The Penn-led study locked down the process, demonstrating that T cells exposed to tumor-derived substances had a considerable reduction in levels of the gene CH25H. Trogocytosis was previously thought to have something to do with the ability of cancer to impede anti-cancer immunity. This gene is known to affect the lipid membranes of cells and can prevent the fusion of two cell membranes, which is required for trogocytosis to take place. They were able to stop trogocytosis by reintroducing a CH25H metabolite.

The researchers was able to find another participant by further analysing the pathway: the gene ATF3, which inhibits the function of CH25H. Trogocytosis was halted by the removal of AFT3 and the capacity of T cells to destroy tumour cells was recovered.

The new discoveries not only point to potential new cancer treatment targets, but they also might have immediate implications for CAR T therapy. Trogocytosis may reduce the efficacy of the modified T cells given by CAR T, so the researchers hypothesised that preventing it might enhance CAR T performance. We reasoned that we should co-express CH25H in the CAR T using what is cleverly referred to as a “armoured CAR” strategy, explains Fuchs. The old CAR T cells proved to be less effective than this.

Delivering CH25H-adorned CAR T cells did, in fact, prolong the lives of cancer-stricken mice compared to CAR T cells without the armour.

Trogocytosis only involves a small proportion of T cells, but according to Fuchs, it may be an unappreciated mechanism in terms of autoimmunity, cancer immunity, and other processes. He and his colleagues plan to investigate the functions of ATF3, CH25H, and other molecules in trogocytosis in the future. He also has high hopes for future researchers to continue these lines of inquiry, bringing the research’s conclusions closer to therapeutic application.




Journal reference:

Lu, Z., et al. (2022) ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes. Cell Metabolismdoi.org/10.1016/j.cmet.2022.08.007.

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